AN0025, a novel antagonist of PGE2-receptor E-type 4 (EP4), in combination with total neoadjuvant treatment of advanced rectal cancer.

PURPOSE: To assess the safety and efficacy of AN0025 in combination with preoperative radiotherapy and chemotherapy in either short course (SCRT) or long course radiotherapy (LCRT) settings for those with locally advanced rectal cancer. PATIENTS AND METHODS: Twenty-eight subjects with locally advanced rectal cancer participated in this multicenter, open-label, Phase Ib trial. Enrolled subjects received either 250 mg or 500 mg of AN0025 once daily for 10 weeks with either LCRT or SCRT with chemotherapy (7 subjects/group). Participants were assessed for safety/efficacy starting from the first dose of study drug administration and were followed for 2 years. RESULTS: No treatment-emergent adverse or serious adverse events meeting dose-limiting criteria were observed, with only 3 subjects discontinuing AN0025 treatment due to adverse events. Twenty-five of 28 subjects completed 10 weeks of AN0025 and adjuvant therapy and were evaluated for efficacy. Overall, 36.0% of subjects (9/25 subjects) achieved a pathological complete response or a complete clinical response, including 26.7% of subjects (4/15 subjects who underwent surgery) who achieved a pathological complete response. A total of 65.4% of subjects had magnetic resonance imaging-confirmed down-staging ≤ stage 3 following completion of treatment. With a median follow-up of 30 months. The 12-month disease-free survival and overall survival were 77.5% (95% confidence interval [CI]: 56.6, 89.2) and 96.3% (95% CI: 76.5, 99.5), respectively. CONCLUSIONS: Treatment with AN0025 administered for 10 weeks along with preoperative SCRT or LCRT did not appear to worsen the toxicity in subjects with locally advanced rectal cancer, was well-tolerated and showed promise in inducing both a pathological and complete clinical response. These findings suggest its activity deserves further investigation in larger clinical trials.

External Fixator Usage and Delayed MRI Scans: A National Survey Study.

OBJECTIVE: To report the current state of institutional protocols regarding the use of MRI in patients with external fixation devices (EFDs) in the United States. DESIGN: National Survey Study. PARTICIPANTS: Practicing orthopaedic surgeons frequenting the Orthopaedic Trauma Association website were invited to participate in this study. RESULTS: Sixty-two eligible orthopaedic surgeons completed the survey. No respondents reported any known harmful complications of MRI use with an EFD. Eight respondents (13%) reported at least one early scan termination because of mild warmth or vibration without any lasting complications. Fifty-six respondents (90%) reported delays to care related to MRI-EFD compatibility labeling, and 27 respondents (48%) reported delayed MRI scans in every patient with an EFD who needed one. Twenty-six surgeons (42%) had modified their practice in some way in response to these barriers. Examples include delaying EFD placement until after MRI, relying on CT arthrograms over MRI for surgical planning, and taking patients to the operating room to remove EFDs temporarily and then replace them. Nineteen respondents (31%) had developed formal protocols to address this issue, but having a written protocol was not associated with any decrease in delays ( P = 0.119). Eighty-nine percent of respondents thought there was a need for a national consensus guideline on this issue. CONCLUSION: Despite no previous reports of harmful complications, MRI utilization is frequently delayed or prevented in patients with EFDs in place. This is a pervasive problem nationally, which persists despite the implementation of written institutional protocols. Additional research is needed, potentially at the national level, to address this common issue. LEVEL OF EVIDENCE: V.

Indications for and Risks Associated With Implant Removal After Pediatric Trauma.

A wide range of implants are used in the treatment of pediatric fractures, including wires, plates, screws, flexible rods, rigid rods, and external fixation devices. Pediatric bones differ from adult bones both mechanically and biologically, including the potential for remodeling. Implants used in pediatric trauma patients present a unique set of circumstances regarding indications, risks, timing of implant removal, weight-bearing restrictions, and long-term sequelae. Indications for implant removal include wire/pin fixation, when substantial growth remains, and infection. When considering implant removal, the risks and benefits must be assessed. The primary risk of implant removal is refracture. The timing of implant removal varies widely from several weeks to a year or more with the option of retention depending on the fracture, type of implant, and skeletal maturity of the patient.

Short versus long cephalomedullary nailing of intertrochanteric fractures: a meta-analysis of 3208 patients.

OBJECTIVES: The purpose of the study was to compare treatment outcomes after short or long cephalomedullary nailing for intertrochanteric femur fractures. DATA SOURCES: A systematic review of perioperative outcomes after short or long cephalomedullary nailing for intertrochanteric femur fractures was performed. The following databases were used: using the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, PubMed (1980-2019), and MEDLINE (1980-2019). The queries were performed in June 2019. STUDY SELECTION: The following search term query was used: "Intramedullary Nail AND Intertrochanteric Fracture OR "Long OR Short Nail AND intertrochanteric Fracture." Studies were excluded if they were "single-arm" studies (i.e., reporting on either long or short CMN but not both), or did not report at least one of the outcomes being meta-analyzed. Furthermore, cadaveric studies, animal studies, basic science articles, editorial articles, surveys and studies were excluded. DATA EXTRACTION: Two investigators independently reviewed abstracts from all identified articles. Full-text articles were obtained for review if necessary, to allow further assessment of inclusion and exclusion criteria. Additionally, all references from the included studies were reviewed and reconciled to verify that no relevant articles were missing from the systematic review. DATA SYNTHESIS: Short nails were associated with statistically significantly less estimated blood loss and operative time compared to long nails. There were no significant differences in transfusion rates, implant failures or overall re-operation rates between implant lengths. Similarly, there was no significant difference in peri-implant fracture between implant lengths. CONCLUSIONS: Overall, the available clinical evidence supports the use of short cephalomedullary nails for the majority of intertrochanteric femur fractures. STUDY DESIGN/LEVEL OF EVIDENCE: Meta-analysis; Level III, therapeutic.

Incidence and Management of Articular Impaction in Geriatric Olecranon Fractures.

INTRODUCTION: Olecranon fractures are common in the elderly. Articular impaction is encountered occasionally, but the incidence and outcomes after treatment of this injury pattern have not been well characterized. METHODS: We evaluated a cohort of geriatric olecranon fractures to determine the incidence of articular impaction and describe a technique for open reduction and internal fixation. RESULTS: Of the 63 patients in our series, 31 had associated intraarticular impaction (49.2%). Patients with articular impaction did not have significantly different rates of postoperative complications (11/31, 35.5% versus 10/31, 32.3%; P = 1.00) or revision surgery (10/31, 32.3% versus 8/31, 25.8%; P = 0.780) compared with those without articular impaction. CONCLUSION: Articular impaction is a common feature of geriatric olecranon fractures. Surgeons must maintain a high index of suspicion and have a surgical plan in place for managing this component of the injury.

Medial Column Support in Pilon Fractures Using Percutaneous Intramedullary Large Fragment Fixation.

SUMMARY: Pilon fractures are complex injuries to the tibial plafond requiring stable fixation in the setting of effective soft tissue management, particularly in high-energy injuries, open fractures, or in geriatric individuals. Medial column support of the distal tibial metaphysis is often an essential component when applying balanced fixation. However, the biologic implications of multiple surgical approaches in the setting of damaged tissue, devitalized bone, or significant bone loss may contribute to increased complications. Percutaneous intramedullary large fragment screws offer both stability and a soft tissue-friendly approach for stabilizing the medial column. Here, we present our technique and indications for medial column support in pilon fractures using percutaneous large fragment fixation, along with our early clinical experience in a case series of 7 patients. At minimum 6-month follow-up, all patients healed their injuries with maintained alignment and without complications or further reoperation. Medial column support with percutaneous large fragment fixation in pilon fractures is a viable option to provide mechanical stability while effectively managing tenuous soft tissue envelopes.

How are peri-implant fractures below short versus long cephalomedullary nails different?

BACKGROUND: Cephalomedullary nails are a commonly used implant for the treatment of many pertrochanteric femur fractures and are available in short and long configurations. There is no consensus on ideal nail length. Relative advantages can be ascribed to short and long intramedullary nails, yet both implant styles share the potentially devastating complication of peri-implant fracture. Determining the clinical sequelae after fractures below nails of different lengths would provide valuable information for surgeons choosing between short or long nails. Thus, the purpose of the study was to compare injury patterns and treatment outcomes following peri-implant fractures below short or long cephalomedullary nails. METHODS: This was a multicenter retrospective cohort study that identified 33 patients referred for treatment of peri-implant fractures below short and long cephalomedullary nails (n = 19 short, n = 14 long). We compared fracture pattern, treatment strategy, complications, and outcomes between these two groups. RESULTS: Short nails were associated with more diaphyseal fractures (odds ratio [OR] 13.75, CI 2.2-57.9, p 0.002), which were treated more commonly with revision intramedullary nailing (OR, infinity; p 0.01), while long nails were associated with distal metaphyseal fractures (OR 13.75, CI 2.2-57.9, p 0.002), which were treated with plate and screw fixation (p 0.002). After peri-implant fracture, there were no differences in blood loss, operative time, weight bearing status, or complication rates based on the length of the initial nail. In patients treated with revision nailing, there was greater estimated blood loss (EBL, median 300 cc, interquartile range [IQR] 250-1200 vs median 200 cc, IQR 100-300, p 0.03), blood product utilization and complication rates (OR 11.1, CI 1.1-135.7, p 0.03), but a trend toward unrestricted post-operative weight-bearing compared to patients treated with plate and screw constructs. CONCLUSION: Understanding fracture patterns and patient outcomes after fractures below nails of different lengths will help surgeons make more informed implant choices when treating intertrochanteric hip fractures. Revision to a long nail for the treatment of fractures at the tip of a short nail may be associated with increased patient morbidity.

Metaphyseal callus formation in pilon fractures is associated with loss of alignment: Is stiffer better?

OBJECTIVE: To assess the relationship between metaphyseal callus formation and preservation of distal tibial alignment in pilon fractures treated with internal plate fixation. DESIGN: Retrospective Review SETTING: Academic Level I Trauma Center PATIENTS: Forty-two patients with AO/OTA type C2 or C3 pilon fractures treated with plate fixation. INTERVENTION: Internal fixation with anterolateral plating, medial plating, or both. Modified Radiographic Union Score in Tibial fracture (mRUST) scores were determined from six-month radiographs. MAIN OUTCOME MEASUREMENTS: Change in lateral and anterior distal tibial angles (LDTA and ADTA) at six months post-operatively. RESULTS: High callus formation (mRUST ≥ 11 at six months) was associated with a greater loss of coronal reduction as measured by LDTA compared to low callus formation (mRUST < 11): 3.8 vs 2.1° (p = .019), with no difference in ADTA change between groups. In a multivariable logistic regression controlling for age, smoking, obesity, and open fracture, higher mRUST scores were a predictor of coronal reduction loss of five or more degrees (OR 1.71, p=.039). Dual column plating did not independently predict maintenance of alignment. CONCLUSIONS: Recent literature has popularized dual column fixation for pilon fractures, but it remains unknown whether increased metaphyseal stiffness enhances or impairs healing. In this series, decreased metaphyseal callus formation was associated with maintained coronal alignment, suggesting that a stiffer mechanical environment may be preferable to prevent short term reduction loss in these complex injuries. LEVEL OF EVIDENCE: III.

Biomechanical Analysis of Retrograde Superior Ramus Screw Fixation Constructs.

OBJECTIVE: To investigate the biomechanical performance of different size and length retrograde superior ramus screws. MATERIALS AND METHODS: A vertical superior ramus fracture was created in osteoporotic composite hemipelvis bone models (Sawbones, Vashon Island, WA). After reduction, 4 fixation groups were created by inserting either a solid 4.5 mm (Depuy Synthes, Paoli, PA) or cannulated 7.0 mm screw (Zimmer, Warsaw, IN) of either 80 mm (short) or 140 mm (long) in length. An intact and an unstabilized osteotomy group were also created. Samples underwent cyclic loading for 5000 cycles with data acquisition at regular intervals. At the end of cyclic loading, load to failure was performed. RESULTS: The displacement after 5000 cycles for 4.5 mm short screws was significantly greater than 4.5 mm long and 7.0 mm short screws. At 5000 cycles, the 4.5-mm short screws had a significantly lower stiffness and lower load to failure than all other screws and were not different from the osteotomy model. CONCLUSIONS: Short 4.5-mm screws demonstrated increased displacement, lower stiffness, and decreased load to failure compared with all other screws. The biomechanical performance of 4.5-mm short screws was no different than unstabilized controls. Longer bicortical screw fixation is suggested when possible. Additional biomechanical and clinical studies are needed to fully understand the significance of these findings.

National Metrics Improved Timeliness of Antibiotic Administration for Open Extremity Fractures.

INTRODUCTION: Antibiotics have been shown to be an essential component in the treatment of open extremity fractures. The American College of Surgeons' Trauma Quality Improvement Program, based on a committee of physician leaders including orthopaedic trauma surgeons, publishes best-practice guidelines for the management of open fractures. Accordingly, it established the tracking of antibiotic timing as a metric with a plan to use that metric before trauma center site reviews. Our hypothesis was that this physician-led effort at the national level would provide the necessary incentive to effect change within our institution. METHODS: A retrospective review of all patients treated at our institution for open extremity fractures was performed over 3 periods separated by 2 quality initiatives. The first initiative was an institution-driven effort to increase awareness and educate specific departments about the importance of prompt antibiotic administration. The second initiative was the tracking of antibiotic order and administration times with quarterly audits following newly published guidelines. RESULTS: Neither antibiotic order placement within 1 hour nor administration within 1 hour improved after our first institution-specific initiative. Both outcome measures significantly improved after the second quality initiative, as did median times from arrival to antibiotic order and administration. CONCLUSIONS: Metrics developed and measured by a physician-led national organization led to practice changes at our hospital. Tracking of antibiotic timing for open fracture treatment was more effective than institutional education of healthcare providers alone. This study suggests that nationally published guidelines, developed and measured by physician leaders, will be found to be relevant by other physicians and can be a powerful tool to drive change.

How do pilon fractures heal? An analysis of dual plating and bridging callus formation.

OBJECTIVES: 1) To determine the effect of single versus dual plate metaphyseal fixation for pilon fractures on callus formation and reoperation rates, 2) to determine the effect of biomechanically matched versus unmatched fixation, and 3) to determine whether patient or surgical factors were independent predictors of bridging callus formation or need for reoperation. DESIGN: Retrospective comparative study. SETTING: Single level one trauma center. PATIENTS: Fifty patients with AO/OTA type C2 or C3 pilon fractures treated with plate fixation. INTERVENTION: Internal fixation with a plate and screw construct, with comparisons made between patients with single versus dual plate fixation, and patients treated with biomechanically matched or unmatched fixation. MAIN OUTCOME MEASUREMENTS: Modified RUST (mRUST) scores at three and six months and reoperation rate. RESULTS: At six months, mean mRUST scores were significantly lower in patients treated with dual metaphyseal plates compared to a single plate (8.7 vs 10.4, p=0.046) There were 15 open fractures; eight were treated with supplemental fixation, while seven were treated with single-column fixation. Open fracture (OR 51.05, p=0.008) was a risk factor for reoperation. Screw density between 0.4 and 0.5 was a protective factor against reoperation (OR 0.03, p=0.026). Biomechanically unmatched fixation did not affect mRUST scores or reoperation rates. CONCLUSIONS: Pilon fractures treated with a single plate had more callus formation six months after surgery compared to those treated with dual plate fixation, and there was no difference in reoperation rates. Screw density between 0.4-0.5 was protective against reoperation. These data may serve as the basis of future work to determine the ideal fixation construct for the frequently comminuted metaphysis in pilon fractures. Further work is necessary to determine whether callus formation in these injuries is desirable. LEVEL OF EVIDENCE: Three.

New Technologies to Image Tumors.

The premise of this book is the importance of the tumor microenvironment (TME). Until recently, most research on and clinical attention to cancer biology, diagnosis, and prognosis were focused on the malignant (or premalignant) cellular compartment that could be readily appreciated using standard morphology-based imaging.

A Novel GUCY2C-CD3 T-Cell Engaging Bispecific Construct (PF-07062119) for the Treatment of Gastrointestinal Cancers.

PURPOSE: Gastrointestinal cancers remain areas of high unmet need despite advances in targeted and immunotherapies. Here, we demonstrate potent, tumor-selective efficacy with PF-07062119, a T-cell engaging CD3 bispecific targeting tumors expressing Guanylyl Cyclase C (GUCY2C), which is expressed widely across colorectal cancer and other gastrointestinal malignancies. In addition, to address immune evasion mechanisms, we explore combinations with immune checkpoint blockade agents and with antiangiogenesis therapy. EXPERIMENTAL DESIGN: PF-07062119 activity was evaluated in vitro in multiple tumor cell lines, and in vivo in established subcutaneous and orthotopic human colorectal cancer xenograft tumors with adoptive transfer of human T cells. Efficacy was also evaluated in mouse syngeneic tumors using human CD3ε transgenic mice. IHC and mass cytometry were performed to demonstrate drug biodistribution, recruitment of activated T cells, and to identify markers of immune evasion. Combination studies were performed with anti-PD-1/PD-L1 and anti-VEGF antibodies. Toxicity and pharmacokinetic studies were done in cynomolgus macaque. RESULTS: We demonstrate that GUCY2C-positive tumors can be targeted with an anti-GUCY2C/anti-CD3ε bispecific, with selective drug biodistribution to tumors. PF-07062119 showed potent T-cell-mediated in vitro activity and in vivo efficacy in multiple colorectal cancer human xenograft tumor models, including KRAS- and BRAF-mutant tumors, as well as in the immunocompetent mouse syngeneic tumor model. PF-07062119 activity was further enhanced when combined with anti-PD-1/PD-L1 treatment or in combination with antiangiogenic therapy. Toxicity studies in cynomolgus indicated a monitorable and manageable toxicity profile. CONCLUSIONS: These data highlight the potential for PF-07062119 to demonstrate efficacy and improve patient outcomes in colorectal cancer and other gastrointestinal malignancies.

Comparison of the molecular and cellular phenotypes of common mouse syngeneic models with human tumors.

BACKGROUND: The clinical success of immune checkpoint inhibitors demonstrates that reactivation of the human immune system delivers durable responses for some patients and represents an exciting approach for cancer treatment. An important class of preclinical in vivo models for immuno-oncology is immunocompetent mice bearing mouse syngeneic tumors. To facilitate translation of preclinical studies into human, we characterized the genomic, transcriptomic, and protein expression of a panel of ten commonly used mouse tumor cell lines grown in vitro culture as well as in vivo tumors. RESULTS: Our studies identified a number of genetic and cellular phenotypic differences that distinguish commonly used mouse syngeneic models in our study from human cancers. Only a fraction of the somatic single nucleotide variants (SNVs) in these common mouse cell lines directly match SNVs in human actionable cancer genes. Some models derived from epithelial tumors have a more mesenchymal phenotype with relatively low T-lymphocyte infiltration compared to the corresponding human cancers. CT26, a colon tumor model, had the highest immunogenicity and was the model most responsive to CTLA4 inhibitor treatment, by contrast to the relatively low immunogenicity and response rate to checkpoint inhibitor therapies in human colon cancers. CONCLUSIONS: The relative immunogenicity of these ten syngeneic tumors does not resemble typical human tumors derived from the same tissue of origin. By characterizing the mouse syngeneic models and comparing with their human tumor counterparts, this study contributes to a framework that may help investigators select the model most relevant to study a particular immune-oncology mechanism, and may rationalize some of the challenges associated with translating preclinical findings to clinical studies.

Comparative Analysis of Mechanism-Associated 3-Dimensional Tibial Plateau Fracture Patterns.

BACKGROUND: The association between tibial plateau fracture morphology and injury force mechanism has not been well described. The aim of this study was to characterize 3-dimensional fracture patterns associated with hypothesized injury force mechanisms. METHODS: Tibial plateau fractures treated in a large trauma center were retrospectively reviewed. Three experienced surgeons divided fractures independently into 6 groups associated with injury force mechanisms proposed from an analysis of computed tomographic (CT) imaging: flexion varus, extension varus, hyperextension varus, flexion valgus, extension valgus, and hyperextension valgus. The fracture lines and comminution zones of each fracture were graphically superimposed onto a 3-dimensional template of the proximal part of the tibia. Fracture characteristics were then summarized on the basis of the fracture maps. The association between injury force mechanism and ligament avulsions was calculated. RESULTS: In total, 353 tibial plateau fractures were included. The flexion varus type pattern was seen in 67 fractures characterized by a primary fracture apex located posteromedially and was frequently associated with concomitant anterior cruciate ligament (ACL) avulsion (44.8%). The extension varus pattern was noted in 60 fractures with a characteristic medial fragment apex at the posteromedial crest or multiple apices symmetrically around the crest and was commonly completely articular in nature (65%). The hyperextension varus pattern was seen in 47 fractures as noted by anteromedial articular impaction, 51% with a fibular avulsion and 60% with posterior tension failure fragments. The flexion valgus pattern was observed in 51 fractures characterized by articular depression posterolaterally, often (58.9%) with severe comminution of the posterolateral cortical rim. The extension valgus patterns in 116 fractures only involved the lateral plateau, with central articular depression and/or a pure split. The hyperextension valgus pattern occurred in 12 fractures denoted by anterolateral articular depression. A moderate positive association was found between flexion varus fractures and ACL avulsions and between hyperextension varus fractures and fibular avulsions. CONCLUSIONS: Tibial plateau fractures demonstrate distinct, mechanism-associated 3-dimensional pattern characteristics. Further research is needed to validate the classification reliability among other surgeons and to determine the potential value in the diagnosis and formulation of surgical protocols.

Biomechanical comparison of bone-screw-fasteners versus traditional locked screws in plating female geriatric bone.

OBJECTIVES: To biomechanically compare plated constructs using nonlocking bone-screw-fasteners with interlocking threads versus locking screws with traditional buttress threads in geriatric female bone. METHODS: Eleven matched pairs of proximal and distal segments of geriatric female cadaveric tibias were used to create a diaphyseal fracture model. Nonlocking bone-screw-fasteners or locking buttress threaded screws were applied to a locking compression plate on the anterolateral aspect of the tibia placed in bridge mode. Specimens were subjected to incrementally increasing cyclic axial load combined with constant cyclic torsion. Total cycles to failure served as a primary outcome measure, with failure defined as 2 mm of displacement or 10 degrees of rotation. Secondary outcome measures included initial stiffness in compression and torsion determined from preconditioning testing and overall rigidity as determined by maximum peak-to-peak axial and rotational motion at 500 cycle intervals during cyclic testing. Group comparisons were made using paired Student's t-tests. Significance was set at p < 0.05. RESULTS: Bone-screw-fastener constructs failed at an average of 40,636 ± 22,151 cycles and locking screw constructs failed at an average of 37,773 ± 8433 cycles, without difference between groups (p = =0.610). Total cycles to failure was higher in the bone-screw-fasteners group for 7 tibiae out of the eleven matched pairs tested. During static and cyclic testing, bone-screw-fastener constructs demonstrated increased initial torsional stiffness (7.6%) and less peak-to-peak displacement and rotation throughout the testing cycle(p < 0.05). CONCLUSIONS: In female geriatric bone, constructs fixed with bone-screw-fasteners incorporate multiplanar interlocking thread geometry and performed similarly to traditional locked plating. These novel devices may combine the benefits of both nonlocking and locking screws when plating geriatric bone.

Posterior Sternoclavicular Dislocation: Do We Need "Cardiothoracic Backup"? Insights From a National Sample.

OBJECTIVES: To describe the incidence of and risk factors for vascular injury associated with P-SCD. METHODS: We used data from the HCUP-NIS from 2015 to 2016 and defined a cohort of patients with sternoclavicular dislocation (SCD) using ICD-10-CM diagnosis codes. We further isolated a subset with P-SCD. We describe the incidence of thoracic vascular injury, demographics, and injury severity score in this cohort. RESULTS: Of an estimated 550 patients who had SCD, 140 (25%) were identified as having a P-SCD. No vascular injuries occurred in the P-SCD cohort. Among all patients with SCD, <2% of patients had a vascular injury, all of whom had an injury severity score ≥15, independent of the vascular injury itself. Among patients with an isolated P-SCD injury (55), overall length of stay was 1.8 days and total charges averaged $29,724.45. There was no mortality among patients with isolated P-SCD. CONCLUSIONS: Here, we report no vascular injuries in the largest known series of P-SCD. Among all patients with SCD, vascular injury was rare, occurring only in severely polytraumatized patients. The recommendation for routine involvement of cardiothoracic surgeons in all cases of P-SCD should be re-examined. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Upregulation of PD­L1 expression by resveratrol and piceatannol in breast and colorectal cancer cells occurs via HDAC3/p300­mediated NF­κB signaling.

Programmed cell death ligand 1 (PD­L1) expressed in cancer cells interacting with its receptor programmed cell death 1 (PD­1) expressed in immune cells represents a regulatory axis linked to the suppression and evasion of host immune functions. The blockade of PD­1/PD­L1 interaction using monoclonal antibodies has emerged as an effective therapy for several solid tumors; however, durable response has been observed in a subset of patients with PD­L1-positive tumors. Thus, the understanding of the mechanisms responsible for the expression of PD­L1 in tumor cells may help to improve the response to PD­L1 blockade therapies. In this study, we investigated whether resveratrol, a grape-derived stilbenoid with immunoregulatory activity, modulates the expression of PD­L1 in breast and colorectal cancer cells. The surface expression of PD­L1 was determined by flow cytometry in cancer cells treated with resveratrol and/or piceatannol. Each stilbenoid alone induced PD­L1 and when used in combination, elicited a synergistic upregulation of PD­L1 in some cell lines. The induction of PD­L1 by the combined use of stilbenoids was most pronounced in the Cal51 triple-negative breast cancer (TNBC) and SW620 colon cancer cells. The observed induction of PD­L1 was transcriptionally mediated by nuclear factor (NF)-κB, as shown by NF­κB reporter assays, the nuclear accumulation of the p65 subunit of NF­κB, inhibition by the IKK inhibitor, BMS­345541, and histone the modification inhibitors, resminostat, entinostat or anacardic acid. Combined treatment with resveratrol and piceatannol also decreased tumor cell survival as indicated by the upregulation of the DNA damaging marker, γH2AX, the cleavage of caspase 3, the downregulation of the survival markers, p38-MAPK/c­Myc, and G1-to-S cell cycle arrest.

Reduction Techniques for Diaphyseal Femur Fractures.

Achieving and maintaining reduction in patients with a diaphyseal femur fracture may be difficult; therefore, thorough preoperative planning is required. To fully prepare for successful surgical management of diaphyseal femur fractures, surgeons must consider appropriate patient positioning and necessary tools, including surgical tables, traction devices, and instruments. Principles of acceptable reduction rely on the restoration of length, alignment, and rotation. Reduction of diaphyseal femur fractures should be attained in the least invasive manner, via percutaneous reduction techniques, if possible, to preserve fracture biology and promote successful fracture healing. Intraoperative assessment of reduction often requires imaging studies of the contralateral extremity as a reference. Intraoperative assessment for associated femoral neck fractures and postoperative clinical examination of the hip and knee are imperative to the successful management of diaphyseal femur fractures. Other reference modalities and clinical examinations are required in patients with bilateral diaphyseal femur fractures.

A CD3-bispecific molecule targeting P-cadherin demonstrates T cell-mediated regression of established solid tumors in mice.

Strong evidence exists supporting the important role T cells play in the immune response against tumors. Still, the ability to initiate tumor-specific immune responses remains a challenge. Recent clinical trials suggest that bispecific antibody-mediated retargeted T cells are a promising therapeutic approach to eliminate hematopoietic tumors. However, this approach has not been validated in solid tumors. PF-06671008 is a dual-affinity retargeting (DART®)-bispecific protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex in the presence of solid tumors expressing P-cadherin. This bispecific molecule elicited potent P-cadherin expression-dependent cytotoxic T cell activity across a range of tumor indications in vitro, and in vivo in tumor-bearing mice. Regression of established tumors in vivo was observed in both cell line and patient-derived xenograft models engrafted with circulating human T lymphocytes. Measurement of in vivo pharmacodynamic markers demonstrates PF-06671008-mediated T cell activation, infiltration and killing as the mechanism of tumor inhibition.